P790: DISTINCT MUTATIONAL PATTERN OF T-CELL LARGE GRANULAR LYMPHOCYTE LEUKEMIA COMBINED WITH PURE RED CELL APLASIA: LOW MUTATIONAL BURDEN OF STAT3
Authors: Sooyong Park, Jiwon Yun, Sung Yoon Choi, Dajeong Jeong, Ja-Yoon Gu, Jee-Soo Lee, Moon-Woo Seong, Yoon Hwan Chang, Hongseok Yun, Hyun Kyung Kim
Journal: HemaSphere (2023)

Topic: 12. Bone marrow failure syndromes incl. PNH - Clinical Background: T-cell large granular lymphocyte leukemia (T-LGL) is a mature neoplasm of T cells. Autoimmune diseases are often associated with T-LGL in Western countries, while pure red cell aplasia (PRCA) is more often reported in Asian countries. Development of PRCA occurs along with various underlying diseases such as thymoma, T-LGL, and autoimmune diseases. It is also a bone marrow failure syndrome (BMFS) along with aplastic anemia and myelodysplastic syndrome (MDS). The discovery of somatic mutations of STAT3 has led to a more optimistic outlook regarding the genetic basis of T-LGL pathogenesis. Activation of STAT3 induced by somatic mutation is thought to facilitate proliferation of T cells. Because mutation of clonal hematopoiesis-related genes in PRCA, aplastic anemia and a subset of T-LGL occurs concomitantly with BMFS, mutational patterns of T-LGL may differ according to the concomitant disorders. Aims: Conduct of the study demonstrated the difference in mutational pattern according to the concomitant PRCA, STAT3 mutation, or treatment response and the association of mutational extent of STAT3 mutation and clinical features. We also examined the frequency of STAT3 and STAT5B mutations in hematologic diseases without T-LGL to diagnose the presence of T-LGL. Methods: High depth of next generation sequencing (NGS) of 84 candidate genes including all genes detected in PRCA or aplastic anemia was performed. Patients diagnosed with T-LGL (n=41) or isolated PRCA (n=3) were enrolled. Patients with T-LGL were divided into two groups; T-LGL alone (n=25) and T-LGL+PRCA (n=16). A review of 591 patients who were requested for an NGS panel of hematologic malignancies was conducted for identification of STAT3 and STAT5B mutation frequencies in hematologic diseases without T-LGL. Two custom targeted NGS panels were used. For T-LGL and/or PRCA, 84 genes reported to show mutation in PRCA or aplastic anemia, STAT3 and STAT5B were used. Sequencing was performed using NovaSeq6000. The median depth of coverage was 1502x. For hematologic diseases without T-LGL, a panel of 103 hematologic malignancy-related genes was used. Sequencing was performed using NextSeq550Dx. The average depths of coverage were >200 x and the cut-off value was set as ≥2% VAF for all samples. Results: No mutation was detected in PRCA (n=3). Of 41 patients with T-LGL or T-LGL+PRCA, STAT3 mutation was detected in 17 patients (41.5%), nine (36.0%) of 25 patients with T-LGL, and eight (50.0%) of 16 patients with T-LGL+PRCA. When aligning with the level of STAT3 VAF, a low level of VAF (<10.0%) was detected in only two patients with T-LGL (22.2%) compared to those with T-LGL+PRCA (87.5%, P=0.015). STAT5B mutations were detected in two patients with STAT3 wild type. Excluding the three patients with a concomitant MDS clone, 65 mutations were detected in 28 genes (33.3%) of all 84 targeted genes in 32 patients with T-LGL or T-LGL+PRCA. After excluding STAT3 mutations, the genes showing frequent mutation included KMT2D (17.1%), TERT (12.2%), SUZ12 (9.8%). Conduct of a retrospective analysis of 591 hematologic patients without T-LGL resulted in identification of three patients with STAT3 (n=1) or STAT5B (n=2) mutations. Summary/Conclusion: The findings of our study suggest that T-LGL combined with PRCA is a unique disease entity that can be classified as a subtype of T-LGL. Routine utilization of high depth NGS testing can provide sensitive detection of concomitant MDS in patients with T-LGL. STAT3 mutations suggest the presence of subclinical T-LGL in hematologic diseases.Keywords: Bone marrow failure, Pure red cell aplasia, Large granular lymphocytic leukaemia, STAT3